Approximately 20% of breast cancers display amplification of the HER2 gene, a genotype historically associated with an aggressive course and poor outcome (Slamon, D. J., et al. Science 235, 177-182 (1987); herein incorporated by reference in its entirety). The development of agents such as trastuzumab and lapatinib that are capable of targeting HER2 represents one of the greatest achievements in clinical oncology providing a prime example for the effectiveness of molecularly targeted therapeutics (Vogel, C. L., et al. J Clin Oncol 20, 719-726 (2002); herein incorporated by reference in its entirety). In women with advanced metastatic breast cancer, the addition of trastuzumab to cytotoxic chemotherapy increases the response rate, time to tumor progression and survival (Vogel, C. L., et al. J Clin Oncol 20, 719-726 (2002); Slamon, D. J., et al. N Engl J Med 344, 783-792. (2001); Vogel, C. L., et al. Oncology 61 Suppl 2, 37-42 (2001); herein incorporated by reference in their entireties). The beneficial effects of trastuzumab in this setting appear to be limited to breast tumors with HER2 amplification (Mass, R. D., et al. Clin Breast Cancer 6, 240-246 (2005); Wolff, A. C., et al. J Clin Oncol 25, 118-145 (2007); herein incorporated by reference in their entireties). These clinical findings supported earlier preclinical data utilizing cell lines and xenografts models which demonstrated that the beneficial effects of HER2 blockade were limited to HER2 amplified breast cancers (Mueller, B. M., et al. Mol Cancer Ther 9, 3024-3032 (2010); herein incorporated by reference in its entirety). The results of these studies prompted the development of standardized laboratory tests to assess HER2 expression. Although treatment decisions are usually based on the HER2 status obtained on the primary tumor, a number of studies have demonstrated discordance between HER2 expression in the primary tumor and at metastatic sites. This discordance is significantly greater when HER2 is analyzed by immunohistochemistry at the protein level then when analyzed for HER2 gene HER2 amplification by FISH (Fabi, A., et al. Clin Cancer Res 17, 2055-2064 (2011); Lipton, A., et al. Cancer 116, 5168-5178 (2010); herein incorporated by reference in their entireties).
Based on the demonstrated clinical efficacy of HER2 blockade in the advanced setting, a number of large randomized clinical trials were initiated to determine whether administration of HER2 blocking agents in the adjuvant setting would prevent recurrence. Reflecting the observation in advanced disease trials that the benefit of HER2 blockade was limited to women whose tumors displayed HER2 amplification, inclusion of patients into adjuvant trials was limited to this patient population. These adjuvant trials demonstrated a remarkable 50% reduction in recurrence rate with the addition of trastuzumab to chemotherapy compared to chemotherapy alone (Joensuu, H., et al. N Engl J Med 354, 809-820 (2006); Piccart-Gebhart, M. J., et al. N Engl J Med 353, 1659-1672 (2005); Romond, E. H., et al. N Engl J Med 353, 1673-1684 (2005); Smith, I., et al. Lancet 369, 29-36 (2007); Spielmann, M., et al. J Clin Oncol 27, 6129-6134 (2009); herein incorporated by reference in their entireties). Long term followings of these patients have confirmed the long term benefits of adjuvant trastuzumab (JCO, 2011). Since HER2 amplified breast cancers have an aggressive natural course, most recurrences occur within 5-7 years suggesting that the flat survival curves after this period may reflect dramatic increase in the cure rates.